Research into new therapeutic strategies for treating pediatric solid tumors has focused on bone and soft-tissue sarcomas (including the Ewing's sarcoma family of tumors, rhabdomyosarcoma, and osteosarcoma) which serve as an excellent "model system" for the exploration of strategies and hypotheses with broad applicability to both pediatric and adult oncology. The overall goal of these protocols is to improve our use of known active agents through dose-intensification and reduction in toxicity. Recent approaches also seek to identify active new agents with novel mechanisms of action in previously untreated, poor-prognosis patients, to develop methods of drug administration to overcome acquired drug resistance, and to interfere with growth-factor/hormone "loops" which may contribute to tumorigenesis. Previous Pediatric Branch protocols demonstrated high activity for intensive vincristine, doxorubicin, and cylophosphamide (VAdriaC) in newly diagnosed sarcoma patients (83-C-73H), and a high level of activity for ifosfamide and etoposide (IE) in those with recurrent tumors (85-C-154). Integration of IE with VAdria into a front-line regimen led to a significant improvement in outcome for patients with localized tumors, but no improvement for those with metastatic disease (86-C-169). Use of rh-GM-CSF produced a modest reduction in the duration of severe neutropenia, however, this benefit was not demonstrated in the majority of patients receiving the growth factor, did not translate into reductions in infectious complications or supportive care requirements, and was offset by a greater degree and duration of thrombocytopenia (88-C-165). Use of ICRF-187 (Dexrazoxane) permitted doxorubicin to be administered more safely and to a higher cumulative dose, with no adverse impact on non- cardiac toxicities, response to chemotherapy, or survival (89-C-07). These companion studies were the only randomized trials of these promising new approaches in pediatric solid tumor patients. Our current front-line sarcoma protocol (93-C-125) builds upon the results of the previous two generations of sarcoma studies. Phase II "window" evaluation of topotecan is ongoing. Significant increases in doxorubicin and cyclophosphamide dose intensities have been achieved. Dexrazoxane has again been shown to be significantly cardioprotective even with a more doxorubicin-intensive regimen. Demonstration of tumor cell contamination of more than 50% of peripheral blood progenitor cell (PBPC) collections has led to use of positive selection techniques. G-CSF-supported PBPC transfusions have permitted the safe administration of monthly cycles of high-dose IE with dose-escalated, "myeloablative" doses of melphalan.